The nervous system is highly susceptible to the effects of age. Aging affects the nervous system in specific and deleterious ways. Aging neurons are less able to repair injury, less able to transmit information, less able to maintain their normal morphology, and are more prone to degeneration and neurodegenerative disease. However, despite the clear evidence for functional loss, the molecular mechanisms that mediate neuronal aging are obscure. This proposal addresses aging within neurons-that is, how do individual neurons respond to age, and how do they regulate this response? At the same time, the ways in which neuronal aging may affect overall lifespan are investigated. The project focuses in particular on the dramatic loss of neuronal ability to repair damaged axons that occurs with age, as well as other aspects of neuronal aging. Preliminary data identify novel and specific cell-biological processes that affect neuronal aging. The project will elucidate the detailed mechanisms that contribute to neuronal aging, test their interdependence, and examine whether different functional aspects of neuronal aging are regulated by different or by common mechanisms. Each Aim is supported by extensive preliminary data, as well as by novel biological concepts and experimental approaches. Completion of these Aims will describe fundamental cellular mechanisms that mediate neuronal aging, and contribute to a more complete understanding of aging in complex organisms with multiple tissue types.